The research team, led by investigators at Capital Medical University in Beijing, combined bioinformatics, flow cytometry and multiplex immunohistochemical staining to chart where LAIR1 is expressed in human gliomas. The answer was unambiguous: LAIR1 is found predominantly on glioma-associated microglia and macrophages, collectively known as GAMs. Patients whose tumours harboured high numbers of LAIR1-expressing GAMs survived significantly less long than those with lower infiltration, establishing the receptor as a marker, and potentially a driver, of aggressive disease.

To test whether LAIR1 merely accompanies poor outcomes or actively causes them, the researchers turned to genetically engineered mice lacking the Lair1 gene. In orthotopic glioma models, in which tumours are implanted within the brain itself, LAIR1 deficiency substantially reduced tumour burden. The effect was traced to the behaviour of the immune cells rather than the tumour cells: when LAIR1 was absent, GAMs displayed enhanced tumoricidal activity in laboratory assays, engulfing tumour cells more readily and mounting stronger anti-tumour responses.

Single-cell and bulk RNA sequencing of LAIR1-high GAMs revealed a strongly immunosuppressive phenotype. These cells expressed molecular programmes associated with dampened T-cell responses, a hallmark of the glioma microenvironment that has repeatedly frustrated immunotherapy efforts. Notably, the team found that LAIR1-high GAMs were linked to the CD47-SIRPα axis, a well-known ‘don’t eat me’ signalling pair in which tumour cells display CD47 on their surface to engage SIRPα on macrophages and shut down engulfment. In mouse models, tumours rich in LAIR1-high GAMs were resistant to anti-PD-1 checkpoint blockade, connecting this receptor to the clinical failure of immunotherapy in brain cancer.

The mechanistic heart of the study concerns a protein called MYH9, the heavy chain of non-muscle myosin IIA. Myosin II motors are well established as physical enablers of phagocytosis: they generate the contractile force needed for a macrophage to extend its membrane around a target and pull it inside. Previous work has shown that myosin II activity must be precisely regulated at the phagocytic synapse, and the new findings place MYH9 at the centre of LAIR1’s suppressive circuit in GAMs.

Using co-immunoprecipitation, PCR arrays, molecular dynamics analysis and CRISPR/Cas9 gene editing, the researchers pieced together the pathway step by step. Collagen I, an abundant component of the glioma extracellular matrix, activates LAIR1 on the surface of GAMs. Once engaged, LAIR1 recruits and activates the phosphatase SHP2, which removes a phosphate group from MYH9 at the amino acid serine 1943. This dephosphorylation event has far-reaching consequences: it prevents the recruitment of USP22, a deubiquitylating enzyme that would otherwise stabilise MYH9 by stripping off ubiquitin tags that mark proteins for destruction.

With USP22 blocked from acting on MYH9, the myosin protein loses its protective deubiquitylation and is degraded. The same logic applies to HIF1α, a transcription factor that USP22 also stabilises and that supports the pro-tumour behaviour of macrophages. The net result is that the phagocytic machinery of the GAM is dismantled: the cell can no longer build the contractile apparatus needed to engulf glioma cells, and the immunosuppressive character of the microenvironment deepens. In this way, a collagen-rich tumour matrix actively disarms the very immune cells that patrol it.

The study’s experimental design was unusually comprehensive. Beyond Lair1-deficient mice, the team used engineered BV2 microglial cell lines, bone marrow-derived macrophages and GAMs isolated directly from patients treated at Beijing Tiantan Hospital. RNA sequencing and targeted PCR arrays defined the transcriptional landscape, while molecular dynamics simulations supported the structural basis of the SHP2-MYH9 interaction. Raw sequencing data were deposited in the NCBI Sequence Read Archive, and the work was approved by the Ethics Committee of Beijing Tiantan Hospital, adding translational weight to the preclinical findings.

The therapeutic implications are considerable. LAIR1 belongs to the LILRB family of inhibitory immune receptors, several of which are being pursued as ‘ innate immune checkpoints’ in cancer. LAIR1 itself has attracted attention because it binds collagen domains and has been implicated in T-cell exhaustion in collagen-dense tumours, in acute myeloid leukaemia development, and in resistance to T-cell attack in hepatocellular carcinoma. Antibody blockade of LAIR1 and LAIR1-directed CAR T cells have already shown enhanced anti-tumour responses in preclinical models, suggesting that a pharmacological toolkit for targeting this receptor is beginning to take shape.

What distinguishes the new work is that it defines a complete, testable signalling axis, from extracellular collagen through LAIR1 and SHP2 to USP22, MYH9 and HIF1α, and ties each link to the functional outcome of phagocytosis in glioma-associated immune cells. If LAIR1 can be safely blocked in patients, the brake on GAM engulfment could be released, potentially converting the largest immune population in glioma from a tumour ally into an attacker. Such a strategy might also sensitise tumours to existing checkpoint inhibitors, addressing the anti-PD-1 resistance that the study directly documents. For a disease in which median survival has barely moved in decades, a molecular switch that reprograms the tumour’s own microenvironment offers a genuinely new line of attack, and one that researchers can now pursue with a clear mechanistic map in hand.

Subject of Research: LAIR1-mediated suppression of phagocytosis in glioma-associated microglia and macrophages

Article Title: LAIR1 suppresses phagocytosis via SHP2/USP22-mediated MYH9 degradation in glioma-associated microglia/macrophages to drive immunosuppression

Article References: Wang, Z., Sun, Q., Li, C., Sun, T., He, Z., Wang, Y., Li, R., Lin, X., Jasiulionis, M. G., Ji, N., Zhang, Y., & Xu, H. (2026). LAIR1 suppresses phagocytosis via SHP2/USP22-mediated MYH9 degradation in glioma-associated microglia/macrophages to drive immunosuppression. British Journal of Cancer. https://doi.org/10.1038/s41416-026-03617-5

Image Credits: AI Generated

DOI: 10.1038/s41416-026-03617-5

Keywords: glioma, LAIR1, phagocytosis, microglia, macrophages, SHP2, USP22, MYH9, CD47-SIRPalpha, immunosuppression, immunotherapy resistance, tumour microenvironment

The research, led by Min Wu, Yi-Fei Yang and Xiang-Ping Du of the Department of Orthopedics at Jiangxi Provincial Children’s Hospital in Nanchang, China, began with a simple observation that belied a complex mechanism. When the team exposed BMSCs to hydrogen peroxide, a standard laboratory approach for mimicking oxidative stress, the levels of SPI1, a transcription factor encoded by the Spi-1 proto-oncogene, dropped sharply. The same decline was visible in an animal model: rats whose ovaries had been removed to induce estrogen-deficiency osteoporosis also showed reduced SPI1 in their bone marrow-derived mesenchymal stem cells. The parallel was striking. In both the culture dish and the diseased skeleton, oxidative stress appeared to strip the cells of a factor they apparently needed to stay young.

To test whether that loss mattered, the researchers forced SPI1 expression back up in stressed cells. The effect was dramatic. Overexpressing SPI1 rescued the senescent phenotype that hydrogen peroxide had induced: the cells regained viability, produced fewer reactive oxygen species, and showed reduced staining for senescence-associated beta-galactosidase, a classic enzymatic marker of cellular aging. Just as importantly, SPI1 restoration preserved the cells’ ability to differentiate into bone-forming osteoblasts, which the team quantified using alizarin red S staining of mineralized matrix. In other words, SPI1 was not simply a bystander that declined as cells aged; it appeared to be an active guardian of both youth and bone-building function in the mesenchymal stem cell compartment.

The next question was how SPI1 exerted this protection. Transcription factors work by binding DNA and switching genes on or off, and the researchers had a specific target in mind: NAMPT, the gene encoding nicotinamide phosphoribosyltransferase, the rate-limiting enzyme of the NAD+ salvage pathway. NAD+ has become one of the most intensively studied molecules in aging biology, serving as a coenzyme for hundreds of redox reactions and as the fuel consumed by sirtuins, a family of deacylating enzymes that regulate stress resistance, mitochondrial function and longevity. Declining NAD+ levels are a hallmark of aged tissues, and boosting NAMPT activity has previously been shown to rejuvenate senescent mesenchymal stem cells. Through chromatin immunoprecipitation and luciferase reporter assays, the team demonstrated that SPI1 binds directly to the NAMPT promoter and transcriptionally activates it, raising NAD+ levels inside the stressed cells. This elevation of NAD+ was the mechanistic bridge between SPI1 and senescence resistance, connecting a transcription factor to one of aging biology’s most celebrated metabolic pathways.

But SPI1 is itself a protein, and proteins in the cellular environment are subject to constant quality control. The ubiquitin-proteasome system tags unwanted proteins with chains of ubiquitin molecules, marking them for destruction. For a transcription factor like SPI1, ubiquitination can mean a short half-life and a rapid collapse of expression under stress. This is where USP22 enters the story. USP22 is a deubiquitinating enzyme, a member of a large family of proteases that remove ubiquitin tags and thereby rescue proteins from degradation. The enzyme has attracted growing attention in recent years for its role in stabilizing key regulatory proteins: it has been shown, for example, to deubiquitinate PPARγ in liver cancer cells and FoxM1 in endometrial stromal cells, and to suppress inflammatory signaling by influencing the NLRP3 inflammasome. The Jiangxi team hypothesized that USP22 might perform the same service for SPI1 in BMSCs.

The experimental evidence supported the hypothesis at every step. Co-immunoprecipitation confirmed that USP22 physically interacts with SPI1 inside the cells. Ubiquitination assays then showed that USP22 removes ubiquitin chains from SPI1, and cycloheximide chase experiments, which block new protein synthesis and reveal how fast existing proteins decay, demonstrated that SPI1 protein persists far longer when USP22 is abundant. With SPI1 stabilized, NAMPT transcription stayed high, NAD+ levels were maintained, and the senescence program was held in check. The final piece of the causal puzzle came from a knockdown experiment: when the researchers silenced SPI1 in cells overexpressing USP22, the protective effects of USP22 largely evaporated. Senescence markers rose again, and osteogenic differentiation faltered, showing that SPI1 is the essential downstream mediator of USP22’s anti-aging action in these cells.

Why does this circuit matter beyond the laboratory? Osteoporosis, which affects hundreds of millions of people worldwide, is fundamentally a disease of failed bone regeneration, in which the balance tips from bone formation to bone resorption. Estrogen deficiency accelerates oxidative stress in the bone marrow, and senescent BMSCs not only fail to produce new osteoblasts but actively worsen the inflammatory milieu. The ovariectomized rat model used in this study reproduces key features of postmenopausal bone loss, and the finding that SPI1 declines in this model suggests that the USP22-SPI1-NAMPT axis may be a plausible therapeutic target. If a drug or gene therapy could raise USP22 activity, or stabilize SPI1 by another means, or simply replenish NAD+ through well-known precursors such as nicotinamide mononucleotide, the senescence cascade in transplanted or endogenous stem cells might be blunted before it begins.

The findings also connect to a much broader scientific conversation about the biology of aging. Cellular senescence was once viewed as a passive consequence of damage accumulation; it is now understood as a tightly regulated program, orchestrated by p53, p21, p16 and chromatin changes, and driven upstream by metabolic deficits such as NAD+ depletion. Sirtuins sit at the junction of metabolism and chromatin, consuming NAD+ as they modify histones and regulatory proteins, which is why the NAD+-sirtuin axis has become a focal point for anti-aging interventions. What this study adds is an upstream control point: a deubiquitinase-transcription factor module that feeds into NAMPT expression and thereby into the entire NAD+ economy of the cell. It suggests that protein stability, not merely gene expression or enzyme activity, may be a decisive lever for keeping stem cells youthful under stress.

There are, of course, important caveats and open questions. USP22 has a complicated double life in the literature: in some contexts it promotes tumor growth and inflammation, and its substrates are numerous and tissue-dependent. Any clinical strategy that elevates USP22 would need to weigh potential oncogenic risks, particularly since SPI1 itself is best known as an oncogene in hematopoietic malignancies, even as the new work assigns it a protective role in mesenchymal stem cells. The current study also relies on cell culture and a rat model; whether the same circuit operates in human bone marrow, and whether it can be safely modulated in patients, remains to be demonstrated. Still, the elegance of the pathway is hard to ignore: oxidative stress degrades SPI1, loss of SPI1 silences NAMPT, silencing of NAMPT drains NAD+, and drained NAD+ leaves stem cells old and bone barren. By inserting USP22 at the top of that cascade, evolution appears to have built a safeguard, and researchers have now found the switch. For an aging global population facing a rising tide of fractures, that switch is worth pulling.

Subject of Research: How the deubiquitinase USP22 protects bone marrow mesenchymal stem cells from oxidative stress-induced senescence

Article Title: USP22 alleviates oxidative stress-induced BMSCs senescence by stabilizing SPI1 protein

Article References: Wu, M., Yang, Y.-F., & Du, X.-P. (2026). USP22 alleviates oxidative stress-induced BMSCs senescence by stabilizing SPI1 protein. Molecular Genetics and Genomics, 301(1), Article 194. https://doi.org/10.1007/s00438-026-02519-8

Image Credits: AI Generated

DOI: 10.1007/s00438-026-02519-8

Keywords: USP22, SPI1, NAMPT, NAD+, bone marrow mesenchymal stem cells, cellular senescence, oxidative stress, deubiquitination, osteoporosis, osteogenic differentiation, sirtuins, protein stability